General Features Of Fibrosis Biology Essay

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Fibrosis is the response of a tissue to injury. The injury can be the result of anything from a wound to a degenerative disease. Fibrosis is a leading cause of damage in the lens and is fibroblast mediated. Fibrosis is the result of a response to an injury where the eye's homeostasis has been disrupted. Within the eye, the lens is vital to sight as it focuses the light entering the eye onto the retina. This means that if the lens is damaged or impaired in any way, the result is a loss of some, if not all vision. Fibrosis is when the extracellular matrix is produced to such excess that it disrupts the normal tissue structure. (1)(3)

General features of fibrosis include hyperproliferation, the transdifferentiation of fibroblasts and epithelial cells to myofibroblasts. Matrix contraction caused by the excessive production, and deposition of the extracellular matrix leads to scarring which is also an indicator of fibrosis. After suffering an injury, if the wound healing response doesn't terminate properly, fibrosis occurs. In a wound healing response, new connective tissue needs to be synthesised. To achieve this, mesenchymal fibroblasts activate meaning that they migrate towards the site of the injury and proliferate. The mesenchymal fibroblasts synthesise high levels of matrix proteins such as collagen and fibronectin. Myofibroblasts is the term used to describe the fibroblasts within the wound. Myofibroblasts express high levels of α-smooth muscle actin, so can be seen as a cause of extracellular matrix contraction. High numbers of myofibroblasts are present whenever fibrosis occurs meaning they must contribute to the scarring which leads to the light scattering caused by fibrosis in the lens. (3)

The lens helps to refract the light that enters the cornea along with the cornea on the retina. It is positioned away from the other tissues and has no innervations (nerve supply) or vascular system. Instead it receives all the nutrients it needs from the surrounding aqueous and vitreous humours. The cells within the lens can be classified in two separate groups firstly the cells within the central anterior epithelium which have been present since embryogenesis and secondly the cells that are present in the peripheral epithelium. These cells are able to migrate, divide and differentiate into lens fibre cells. It is the lens fibre cells that make up the majority of the lens. If the normal lens structure is disrupted then a fibrotic change can be triggered. (1)

To study fibrosis, we need to be able to study even the smallest changes to the normal system. To study fibrosis, the models that can be used are tissue cultures, cell lines and transgenic models. Clinical data for fibrosis can be collected as well as post- mortem analysis of the lens. Fibrotic diseases such as anterior subcapsular cataract and posterior capsule opacification can be studied to allow better understanding of fibrosis overall. (1)

Anterior subcapsular cataract (ASC) is the name given to light scattering caused by fibrosis. It is the least common form of cataract within the UK however it is more common in the east. During anterior subcapsular cataract, the anterior lens capsule both thickens and folds and the cells in these areas start to show myofibroblast morphology. This means the cells become spindle shaped, get longer and show evidence (through staining) for alpha smooth muscle actin (αSMA), which is a marker for cataract. Due to the transdifferentiation of the lens epithelial cells, a big amount of extracellular matrix proteins for example type I and III collagen and fibronectin are produced within the lens capsule even though they are not normally present within the lens capsule. (1)

Posterior capsule opacification (PCO) is another typical fibrotic disease, meaning that it in response to injury it demonstrates hyperproliferation (a high rate of cell division), myofibroblast formation as well as matrix deposition and contraction. (1)Posterior capsule opacification (PCO) is a condition that can occur after surgery. It is also the most common condition to occur after cataract surgery. Cataract surgery allows light to once again pass through the lens unhindered allowing vision to be restored. In most operations the lens is replaced by an intraocular lens which is placed within a capsular bag. The capsular bag includes part of the anterior and posterior capsule. However in some cases, after the operation has taken place, there will still be some lens epithelial cells that have remained along the anterior capsule. These cells will begin to multiply and start to inhabit the bare areas of the anterior capsule as well as the posterior capsule that had been free of cells prior. As the cells cover the posterior capsule, they inevitably impinge upon the visual axis. The light path will still be unaltered if there is only a thin layer of cells present however any changes to the cell organisation and matrix, will begin to cause light scatter that can affect vision. (1)

Transforming growth factor (TGFβ) is a profibrotic protein that is seen as the key to the fibrotic response within the eye. TGFβ is present in an inactive form within the aqueous humour of the eye however if the lens suffers damage then the active forms of TGFβ are raised within the eye. Proteins such as α2-macroglobulin (which have a high affinity for free active TGFβ) are present within the ocular humour and regulate TGFβ activity under normal condition. However after suffering trauma, wound healing responses are initiated which lead to increased TGFβ activity due to the stimulation by TGFβ activators such as plasmin proteases MMP2 and 9 which encourage matrix degradation and thrombospondin-1 which modulates cell adhesion, supports angiogenesis and reconstruction of the matrix. TGFβ activity is also encouraged by rising levels of reactive oxygen species. There are three isoforms of TGFβ (1,2 and 3). All three isoforms with raised levels of TGFβ2 have been found present in tissue taken from eyes that had experienced cataract surgery. The most prevalent isoform found within the eye is TGFβ2. The other two forms can still be activated if injury has been sustained for example, after cataract surgery. (1)(2)

Transforming Growth Factor has been linked to both ASC and PCO. Analysis has shown that activated TGFβ can bring about the specific cellular reactions that are key to fibrosis such as the epithelial cells transdifferentiating to mesenchymal cells and the rise in extracellular matrix production. The promotion of the lens epithelial cells to transdifferentiate to myofibroblast phenotype is one of the chief effects of TGFβ. High levels of αSMA and fibronectin are present within ASC tissue. Studies have shown that TGFβ induces ASC in rat lenses. Matrix wrinkling of the posterior capsule and the presence of fibrotic markers such as αSMA, was observed during the analysis of a capsular bag from a donor who had undergone cataract surgery. The same effects of the TGFβ could be seen in vitro. TGFβ induces contraction of the extracellular matrix of the lens capsule forming wrinkles which in turn causes the light scatter which can in cases of severity lead to loss of vision. Smad proteins provide the main intracellular signalling system for TGFβ. (1)(2)

Fibrotic diseases of the lens, in particular PCO, can be studied by various methods. Effects such as matrix deposition and contraction, cell growth and transdifferentiation can all studied from cell lines. In vitro capsular bag models, lens explants and other tissue culture models have been used to study fibrosis. One reason may be because these they have the same cellular structure as they would in vivo. The cells can also grow on their own natural matrix. The lens cells from such tissue cultures can also be sustained for long amounts of time in serum free medium meaning it is without any supplements. This means, the culture conditions can be carefully controlled so the data is easier to interpret than the data from more complex systems. Myofibroblasts which have been for a long time have been implicated as being profibrogenic. However it was the work that was done on the lens and the lung that has now started to suggest that myofibroblasts may actually have a protective role by regulating the fibrotic response proving how useful the lens can be as a model for fibrosis. (1)

To conclude, the lens provides an excellent model for fibrosis due to the number of fibrotic diseases that affect the eye. Anterior subcapsular cataract and posterior capsule opacification both lead to vision loss (and blindness in severe cases) due the fibrotic effects that lead to light scatter within the eye. These fibrotic effects have been found to be induced by TGFβ. Blindness caused by fibrosis affects many millions of people across the world. Proving the lens is an excellent model on which to study fibrosis as the results could be beneficial to so many lives.(1)